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Phase 2 Trial of Indoximod With Chemotherapy and Radiation for Children With Progressive Brain Tumors or Newly Diagnosed DIPG
Indoximod was developed to inhibit the IDO (indoleamine 2,3-dioxygenase) enzymatic pathway, which is important in the natural regulation of immune responses. This potent immune suppressive mechanism has been implicated in regulating immune responses in settings as diverse as infection, tissue/organ transplant, autoimmunity, and cancer. By inhibiting the IDO pathway, we hypothesize that indoximod will improve antitumor immune responses and thereby slow the growth of tumors. The central clinical hypothesis for the GCC1949 study is that inhibiting the pivotal IDO pathway by adding indoximod immunotherapy during chemotherapy and/or radiation is a potent approach for breaking immune tolerance to pediatric tumors that will improve outcomes, relative to standard therapy alone. This is an NCI-funded (R01 CA229646, MPI: Johnson and Munn) open-label phase 2 trial using indoximod-based combination chemo-radio-immunotherapy for treatment of patients age 3 to 21 years who have progressive brain cancer (glioblastoma, medulloblastoma, or ependymoma), or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Statistical analysis will stratify patients based on whether their treatment plan includes up-front radiation (or proton) therapy in combination with indoximod. Central review of tissue diagnosis from prior surgery is required, except non-biopsied DIPG. This study will use the "immune-adapted Response Assessment for Neuro-Oncology" (iRANO) criteria for measurement of outcomes. Planned enrollment is up to 140 patients.
Eligibility Criteria
Inclusion Criteria
- 1Diagnosis:
- 2Progressive disease with histologically proven initial diagnosis of glioblastoma, medulloblastoma, or ependymoma; With confirmation of progression by either MRI or CSF analysis; Measureable disease is not required for study entry; Patients with progressive disease must have been previously treated with therapeutic radiation as part of treatment for the initial brain cancer diagnosis or for a prior relapse.
- 3Newly diagnosed DIPG (diffuse intrinsic pontine glioma) with no prior therapy (including no prior radiation); Biopsy is not required for DIPG.
- 4Central review of tissue diagnosis is required, except non-biopsied DIPG; Archival tumor tissue must be located and available prior to study entry.
- 5Patients with metastatic disease are eligible.
- 6Lansky or Karnofsky performance status score must be ≥ 50%.
- 7Adequate renal function: creatinine ≤ 1.5-times upper limit of age-adjusted normal.
- 8Adequate liver function:
- 9ALT ≤ 5-times upper limit of normal.
- 10Total bilirubin ≤ 1.5-times upper limit of normal.
- 11Adequate Bone marrow function:
- 12Absolute neutrophil count (ANC) ≥ 750/mcL.
- 13Platelets ≥ 75,000/mcL (transfusion independent).
- 14Hemoglobin ≥ 8 g/dL (transfusion independent).
- 15Central nervous system: seizure disorders must be well controlled on antiepileptic medication.
- 16Prior therapy
- 17DIPG patients must not have been treated with any prior radiation or medical therapy.
- 18Patients previously treated with indoximod are excluded.
- 19Patients previously treated with any other immunotherapy agent, including other IDO-targeted drugs, are eligible for enrollment.
- 20Patients previously treated with chemotherapy drugs included in this protocol are eligible for enrollment.
- 21Patients must be 14 days from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions:
- 22Temozolomide dosed at or above 150 mg/m2 (allowed, but must be at least 21 days from the last dose of temozolomide).
- 23Must be 28 days from administration of antibody-based therapies (e.g., bevacizumab), tumor-directed vaccines, or cellular immune therapies (e.g., T cells, NK cells, etc).
- 24Must be 56 days from administration of tumor-directed therapies using infectious agents (e.g., viruses, bacteria, etc).
- 25Pregnant women are excluded from this study, where pregnancy is confirmed by a positive urine or serum hCG laboratory test.
- 26Patients must be able to swallow pills.
- 27.
Exclusion Criteria
- 1Patients who cannot swallow indoximod pills are excluded.
- 2Patients previously treated with indoximod are excluded.
- 3Patients with DIPG who have been treated with any prior radiation or medical therapy are excluded.
- 4Midline glioma that does not include significant brain stem involvement is not considered DIPG for enrollment purposes, and is excluded.
- 5Patients with active systemic infection requiring treatment, including any HIV infection or toxoplasmosis, are excluded.
- 6Patients with active autoimmune disease that requires systemic therapy are excluded.
- 7Pregnant women are excluded
Locations
5 sites participating in this study
Emory University, Children's Heathcare of Atlanta
Druid Hills, Georgia 30322
Augusta University, Georgia Cancer Center
Augusta, Georgia 30912
Theodore S Johnson, MD, PhD
Dana-Farber Cancer Institute
Boston, Massachusetts 02215